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Cold Spring Harbor Perspectives in... Aug 2023Cholesterol is an essential lipid species of mammalian cells. Cells acquire it through synthesis in the endoplasmic reticulum (ER) and uptake from lipoprotein particles.... (Review)
Review
Cholesterol is an essential lipid species of mammalian cells. Cells acquire it through synthesis in the endoplasmic reticulum (ER) and uptake from lipoprotein particles. Newly synthesized cholesterol is efficiently distributed from the ER to other organelles via lipid-binding/transfer proteins concentrated at membrane contact sites (MCSs) to reach the -Golgi network, endosomes, and plasma membrane. Lipoprotein-derived cholesterol is exported from the plasma membrane and endosomal compartments via a combination of vesicle/tubule-mediated membrane transport and transfer through MCSs. In this review, we provide an overview of intracellular cholesterol trafficking pathways, including cholesterol flux from the ER to other membranes, cholesterol uptake from lipoprotein donors and transport from the plasma membrane to the ER, cellular cholesterol efflux to lipoprotein acceptors, as well as lipoprotein cholesterol secretion from enterocytes, hepatocytes, and astrocytes. We also briefly discuss human diseases caused by defects in these processes and therapeutic strategies available in such conditions.
Topics: Animals; Humans; Cell Membrane; Endoplasmic Reticulum; Cholesterol; Biological Transport; Lipoproteins; Mammals
PubMed: 37277190
DOI: 10.1101/cshperspect.a041404 -
Nature Reviews. Molecular Cell Biology Jun 2024Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular... (Review)
Review
Ferroptosis is a non-apoptotic cell death mechanism characterized by iron-dependent membrane lipid peroxidation. Here, we review what is known about the cellular mechanisms mediating the execution and regulation of ferroptosis. We first consider how the accumulation of membrane lipid peroxides leads to the execution of ferroptosis by altering ion transport across the plasma membrane. We then discuss how metabolites and enzymes that are distributed in different compartments and organelles throughout the cell can regulate sensitivity to ferroptosis by impinging upon iron, lipid and redox metabolism. Indeed, metabolic pathways that reside in the mitochondria, endoplasmic reticulum, lipid droplets, peroxisomes and other organelles all contribute to the regulation of ferroptosis sensitivity. We note how the regulation of ferroptosis sensitivity by these different organelles and pathways seems to vary between different cells and death-inducing conditions. We also highlight transcriptional master regulators that integrate the functions of different pathways and organelles to modulate ferroptosis sensitivity globally. Throughout this Review, we highlight open questions and areas in which progress is needed to better understand the cell biology of ferroptosis.
Topics: Ferroptosis; Humans; Animals; Lipid Peroxidation; Iron; Mitochondria; Lipid Metabolism; Cell Membrane; Oxidation-Reduction
PubMed: 38366038
DOI: 10.1038/s41580-024-00703-5 -
Trends in Cell Biology Feb 2024Exosomes are specialized cargo delivery vesicles secreted from cells by fusion of multivesicular bodies (MVBs) with the plasma membrane (PM). While the function of... (Review)
Review
Exosomes are specialized cargo delivery vesicles secreted from cells by fusion of multivesicular bodies (MVBs) with the plasma membrane (PM). While the function of exosomes during physiological and pathological events has been extensively reported, there remains a lack of understanding of the mechanisms that regulate exosome biogenesis, secretion, and internalization. Recent technological and methodological advances now provide details about MVB/exosome structure as well as the pathways of exosome biogenesis, secretion, and uptake. In this review, we outline our current understanding of these processes and highlight outstanding questions following on recent discoveries in the field.
Topics: Humans; Exosomes; Cell Membrane; Multivesicular Bodies; Biological Transport
PubMed: 37507251
DOI: 10.1016/j.tcb.2023.06.006 -
Nature Immunology Jul 2023The regulated disruption of the plasma membrane, which can promote cell death, cytokine secretion or both is central to organismal health. The protein gasdermin D... (Review)
Review
The regulated disruption of the plasma membrane, which can promote cell death, cytokine secretion or both is central to organismal health. The protein gasdermin D (GSDMD) is a key player in this process. GSDMD forms membrane pores that can promote cytolysis and the release of interleukin-1 family cytokines into the extracellular space. Recent discoveries have revealed biochemical and cell biological mechanisms that control GSDMD pore-forming activity and its diverse downstream immunological effects. Here, we review these multifaceted regulatory activities, including mechanisms of GSDMD activation by proteolytic cleavage, dynamics of pore assembly, regulation of GSDMD activities by posttranslational modifications, membrane repair and the interplay of GSDMD and mitochondria. We also address recent insights into the evolution of the gasdermin family and their activities in species across the kingdoms of life. In doing so, we hope to condense recent progress and inform future studies in this rapidly moving field in immunology.
Topics: Intracellular Signaling Peptides and Proteins; Gasdermins; Pyroptosis; Interleukin-1; Cell Membrane; Inflammasomes
PubMed: 37277654
DOI: 10.1038/s41590-023-01526-w -
Cell Apr 2024The membrane protein NINJ1 mediates plasma membrane rupture in pyroptosis and other lytic cell death pathways. Here, we report the cryo-EM structure of a NINJ1 oligomer...
The membrane protein NINJ1 mediates plasma membrane rupture in pyroptosis and other lytic cell death pathways. Here, we report the cryo-EM structure of a NINJ1 oligomer segmented from NINJ1 rings. Each NINJ1 subunit comprises amphipathic (⍺1, ⍺2) and transmembrane (TM) helices (⍺3, ⍺4) and forms a chain of subunits, mainly by the TM helices and ⍺1. ⍺3 and ⍺4 are kinked, and the Gly residues are important for function. The NINJ1 oligomer possesses a concave hydrophobic side that should face the membrane and a convex hydrophilic side formed by ⍺1 and ⍺2, presumably upon activation. This structural observation suggests that NINJ1 can form membrane disks, consistent with membrane fragmentation by recombinant NINJ1. Live-cell and super-resolution imaging uncover ring-like structures on the plasma membrane that are released into the culture supernatant. Released NINJ1 encircles a membrane inside, as shown by lipid staining. Therefore, NINJ1-mediated membrane disk formation is different from gasdermin-mediated pore formation, resulting in membrane loss and plasma membrane rupture.
Topics: Cell Membrane; Humans; Cryoelectron Microscopy; Cell Adhesion Molecules, Neuronal; Animals; Mice; HEK293 Cells; Pyroptosis; Models, Molecular; Membrane Proteins; Phosphate-Binding Proteins
PubMed: 38614101
DOI: 10.1016/j.cell.2024.03.008 -
Nature Reviews. Molecular Cell Biology Feb 2024Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a family of small conserved eukaryotic proteins that mediate membrane fusion between... (Review)
Review
Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) are a family of small conserved eukaryotic proteins that mediate membrane fusion between organelles and with the plasma membrane. SNAREs are directly or indirectly anchored to membranes. Prior to fusion, complementary SNAREs assemble between membranes with the aid of accessory proteins that provide a scaffold to initiate SNARE zippering, pulling the membranes together and mediating fusion. Recent advances have enabled the construction of detailed models describing bilayer transitions and energy barriers along the fusion pathway and have elucidated the structures of SNAREs complexed in various states with regulatory proteins. In this Review, we discuss how these advances are yielding an increasingly detailed picture of the SNARE-mediated fusion pathway, leading from first contact between the membranes via metastable non-bilayer intermediates towards the opening and expansion of a fusion pore. We describe how SNARE proteins assemble into complexes, how this assembly is regulated by accessory proteins and how SNARE complexes overcome the free energy barriers that prevent spontaneous membrane fusion.
Topics: SNARE Proteins; Membrane Fusion; Cell Membrane
PubMed: 37848589
DOI: 10.1038/s41580-023-00668-x -
Nature Communications Oct 2023Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain,...
Niemann-Pick C1-like 1 (NPC1L1) is essential for intestinal cholesterol absorption. Together with the cholesterol-rich and Flotillin-positive membrane microdomain, NPC1L1 is internalized via clathrin-mediated endocytosis and transported to endocytic recycling compartment (ERC). When ERC cholesterol level decreases, NPC1L1 interacts with LIMA1 and moves back to plasma membrane. However, how cholesterol leaves ERC is unknown. Here, we find that, in male mice, intracellular bile acids facilitate cholesterol transport to other organelles, such as endoplasmic reticulum, in a non-micellar fashion. When cholesterol level in ERC is decreased by bile acids, the NPC1L1 carboxyl terminus that previously interacts with the cholesterol-rich membranes via the ALAL residues dissociates from membrane, exposing the QKR motif for LIMA1 recruitment. Then NPC1L1 moves back to plasma membrane. This study demonstrates an intracellular cholesterol transport function of bile acids and explains how the substantial amount of cholesterol in NPC1L1-positive compartments is unloaded in enterocytes during cholesterol absorption.
Topics: Animals; Male; Mice; Biological Transport; Cell Membrane; Cholesterol; Intestinal Absorption; Membrane Transport Proteins
PubMed: 37833289
DOI: 10.1038/s41467-023-42179-5 -
The EMBO Journal Apr 2024Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent accumulation of oxidized phospholipids in cellular membranes, culminating in plasma...
Ferroptosis is a regulated form of necrotic cell death caused by iron-dependent accumulation of oxidized phospholipids in cellular membranes, culminating in plasma membrane rupture (PMR) and cell lysis. PMR is also a hallmark of other types of programmed necrosis, such as pyroptosis and necroptosis, where it is initiated by dedicated pore-forming cell death-executing factors. However, whether ferroptosis-associated PMR is also actively executed by proteins or driven by osmotic pressure remains unknown. Here, we investigate a potential ferroptosis role of ninjurin-1 (NINJ1), a recently identified executor of pyroptosis-associated PMR. We report that NINJ1 oligomerizes during ferroptosis, and that Ninj1-deficiency protects macrophages and fibroblasts from ferroptosis-associated PMR. Mechanistically, we find that NINJ1 is dispensable for the initial steps of ferroptosis, such as lipid peroxidation, channel-mediated calcium influx, and cell swelling. In contrast, NINJ1 is required for early loss of plasma membrane integrity, which precedes complete PMR. Furthermore, NINJ1 mediates the release of cytosolic proteins and danger-associated molecular pattern (DAMP) molecules from ferroptotic cells, suggesting that targeting NINJ1 could be a therapeutic option to reduce ferroptosis-associated inflammation.
Topics: Humans; Alarmins; Ferroptosis; Necrosis; Cell Death; Cell Membrane; Nerve Growth Factors; Cell Adhesion Molecules, Neuronal
PubMed: 38396301
DOI: 10.1038/s44318-024-00055-y -
Comprehensive Physiology Dec 2023Electrical mechanosensing is a process mediated by specialized ion channels, gated directly or indirectly by mechanical forces, which allows cells to detect and... (Review)
Review
Electrical mechanosensing is a process mediated by specialized ion channels, gated directly or indirectly by mechanical forces, which allows cells to detect and subsequently respond to mechanical stimuli. The activation of mechanosensitive (MS) ion channels, intrinsically gated by mechanical forces, or mechanoresponsive (MR) ion channels, indirectly gated by mechanical forces, results in electrical signaling across lipid bilayers, such as the plasma membrane. While the functions of mechanically gated channels within a sensory context (e.g., proprioception and touch) are well described, there is emerging data demonstrating functions beyond touch and proprioception, including mechanoregulation of intracellular signaling and cellular/systemic metabolism. Both MR and MS ion channel signaling have been shown to contribute to the regulation of metabolic dysfunction, including obesity, insulin resistance, impaired insulin secretion, and inflammation. This review summarizes our current understanding of the contributions of several MS/MR ion channels in cell types implicated in metabolic dysfunction, namely, adipocytes, pancreatic β-cells, hepatocytes, and skeletal muscle cells, and discusses MS/MR ion channels as possible therapeutic targets. © 2024 American Physiological Society. Compr Physiol 14:5269-5290, 2024.
Topics: Humans; Ion Channels; Signal Transduction; Cell Membrane; Mechanotransduction, Cellular
PubMed: 38158369
DOI: 10.1002/cphy.c230005 -
Cold Spring Harbor Perspectives in... Oct 2023The sorting and trafficking of lipids between organelles gives rise to a dichotomy of bulk membrane properties between organelles of the secretory and endolysosome... (Review)
Review
The sorting and trafficking of lipids between organelles gives rise to a dichotomy of bulk membrane properties between organelles of the secretory and endolysosome networks, giving rise to two "membrane territories" based on differences in lipid-packing density, net membrane charge, and bilayer leaflet asymmetries. The cellular organelle membrane dichotomy emerges from ER-to-PM anterograde membrane trafficking and the synthesis of sphingolipids and cholesterol flux at the -Golgi network, which constitutes the interface between the two membrane territories. Organelle homeostasis is maintained by vesicle-mediated retrieval of bulk membrane from the distal organelles of each territory to the endoplasmic reticulum or plasma membrane and by soluble lipid transfer proteins that traffic particular lipids. The concept of cellular membrane territories emphasizes the contrasting features of organelle membranes of the secretory and endolysosome networks and the essential roles of lipid-sorting pathways that maintain organelle function.
Topics: Endoplasmic Reticulum; Cell Membrane; Protein Transport; Biological Transport; Lipids
PubMed: 37487627
DOI: 10.1101/cshperspect.a041397